Diastereoisomeric substituted propanes and processes for their preparation



United States Patent 3 2,727,072 1C6 Patented Dec. 13, 1955 DIASTEREOISOMERIC SUBSTITUTED PROPANES AND PROCESSES FOR THEIR PREPARATION No Drawing. Application April 16, 1951, Serial No. 221,336

Claims priority, application France July 7, 1950 11 Claims. (Cl. 260562) This invention relates to new diastereoisomeric substituted propanes and to processes for their preparation.

By analogy with the nomenclature adopted by Rebstock et al. (J. A. C. 8., vol. 71, pp. 2458-2473) in connection with the diastereoisomeric amido diol, 2-dichloracetamido-l-p-nitrophenylpropane 1:3-diol, an optically active isomer of which is known by the common name chloroamphenicol, structural isomeric forms are herein referred to as erythro and threo respectively While the racemic mixture and individual optical isomers corresponding to each of these structural isomeric forms are designated DL, L and D respectively.

The substituted propanes of the present invention are the racemic and optically isomeric threo 2-dichloracetamido-l-p-nitrophenyl-l :3-dichloropropanes conforming to the conventional formula:

According to a preferred feature of this invention, these new tetrachloro compounds are prepared by treating an erythro form of 2-dichloromethyl-4-p-nitrophenylhydroxymethyl-A -oxazolinez OH N (L (brick n with thionyl chloride under anhydrous conditions at a sufficiently high temperature to bring about substitution of the a-hYClI'OXY group by a chlorine atom. The process is conveniently effected by heating a mixture of the oxazoline and purified thionyl chloride under reflux until the reaction has been completed.

Other processes which can be employed for the prep aration of the compounds of the invention are, however, as follows:

(a) the action of hydrogen chloride under anhydrous conditions at elevated temperature (100 C. is suitable) upon the racemates or optical isomeric forms of threo 2-dichloracetamido-1-p-nitrophenyl-3-chloropropane l-ol or of threo Z-dichloracetamido-l-p-nitrophenylpropane 1:3-diol or of threo 2-dichloromethyl-4-p-nitrophenylhydroxymethyl-A -oxazoline, the reaction being preferably effected in an inert organic solvent medium such as dioxane;

(b) the action of thionyl chloride under anhydrous conditions with heating under refiux on the racemate or optically isomeric forms of erythro 2-dichloracetamido-lp-nitrophenyl-3-chloropropane l-ol.

It will be appreciated that since the starting material used in the aforesaid processes can exist in optically isomeric forms, it is necessary, if a particular optical isomer of the final product is to be obtained either to use the starting material in the form of the corresponding isomer or to resolve the racemate produced in the processes hereinbefore described. For the processes employing an erythro starting material, it is necessary to use either the racemic erythro compound with subsequent resolution, or to use the L-erythro isomer if the intended final product is the D-threo tetrachloro compound as the process involves epimerisation reversing the configuration about the alpha carbon atom. For the processes using, however, a D-threo or L-threo starting material the product has, of course, correspondingly the D-threo or L-threo form, respectively, since in these cases the conversion does not involve epimerisation.

The erythro 2 dichloracetamido 1-p-nitrophenyl-3- chloropropane-l-ols used as starting materials may be prepared from a-dichloracetamido-p-hydroxy-p-nitropropiophenone (U. S. Patent 2,515,239) by reaction with thionyl chloride to produce a-dichloracetamido-fl-chlorop-nitropropiophenone and reducing the zit-dichloracetamido-,8-chloro-p-nitropropiophenone as obtained with aluminum isopropylate.

212,482, filed February 23, 1951.

The erythro-2-dichloromethyl-4-p-nitrophenyl-hydroxymethyl-A -oxazoline starting materials can be produced from the erythro-2-dichloracetamido-1-p-nitrophenyl-3- chloropropane-l-ol by the action of aqueous alkali. This method is described in detail in the application of Robert M. Jacob, Serial No. 212,481, filed February 23, 1951, now U. S. Patent 2,702,804.

The threo-Z-dichloracetamido-1-p-nitrophenyl-3-chloropropane-l-ol starting materials can be produced by reactchloropropane-l-ol with aqueous alkali. This method is 1 described in detail in the application of Robert M. Jacob, Serial No. 212,481, filed February 23, 1951.

The compounds of the present invention are useful intermediates for the production of antibiotics and for the production of other chemical compounds having therapeutic properties as well as other intermediates useful in the production of substances having therapeutic properties. For example, a 2-dichloracetamido-l-p-nitro phenyl-l,3-dichloropropane of the present invention can be cyclicized with dilute alkali to obtain the, corresponding 2-dichloromethyl-5-p-nitrophenyhA -oxazoline as described and claimed in copending application 221,335 filed April 16, 1951.

Said oxazoline can be treated with dilute hydrochloric acid followed by neutralization to produce a 2-dichloracetamido-l-p-nitrophenyl-3-chloropropane-l-ol as described in copending application 212,482 filed February 23, 1951. Said compound can be cyclicized with dilute sodium hydroxide at room temperature to obtain a 2-dichloromethyl-4-p-nitrophenylhydroxymethyl-A -oxazoline as described in copending application Serial No. 212,481 filed February 23, 1951.

The said oxazoline can be dissolved in dilute hydrochloric acid at a temperature of 50 C. or below followed 2 by neutralization with aqueous ammonia in the cold to obtain a 2-dichloracetamido-l-p-nitrophenylpropane-1,3- diol as described in the application of Ronald Slack, S erial No. 199,937, filedDecember 8, 1950, now abahdotie'd,

D-(- isomer being known as chloramphenieol.

The present invention is illustrated by the following '5 examples. In these examples, M. P. (cap.) indicates melt- This method is described indetail in the application of Robert M. Jacob, Serial No.

ing points determined by the capillary tube method and M; P. {Maq.) the instantaneous melting point as determined on the Maquenne block.

Example I 2 g. of Dh-erythro 2-dichloromethyl-4-p-nitrophenylhydroxymethyl-n -oxazoline, M. P. (cap.)=l67 C., are heated under reflux for 1 hour and a half with 2.4 c.c. of pure thionyl chloride. On leaving the reaction mixture to @001, a crystalline precipitate is formed, which is filtcre'd off and washed with anhydrous ether. On drying in vacuo in the presence of potash pellets, there is obtained 1.4 g. of DL-threo 2-dichloracetamido-l-p-nitrophe'iryl-lz-3 dichloropropane of M. P. (cap.)=l36- 137 C.

Example II A solution of 656 g. of L-threo 2-dic hloromethyl-4-pnitrophenylhydroxyme'thyl-A -oxazoline of M. P. (Maq =142-143f C; [a] =+17655' (c=5% in ethyl 'ac'etate) 'in 66 c.c. of dioxane containing 13% by weight of dry hydrochloric acid is heated on the water bath in a sealed tube for 1 hour at 100 'C; The mixture is taken -to dryness by distillation in vacuo in the cold; the white crystalline residue is washed with 200 c. c. of water, filtered oil and recrystallised from 30 c. c. of methyl alcohol. After filtering, the product is washed with 2 x -3 c. c. or methyl alcohol and dried in vacuo. There is thus obtained 4.5 g. of L-threo Z-dichIor'aceta'midO-I- p nitroph'enyl-l:3-dichloropropane, M. P. (Maq.)=l52- 152.5 C. '[aIl =+920'-+ -20' (c=6% in ethyl acetate).

Example III Example IV Proceeding as in Example I starting from 0.34 g'. of L-c'rythro 2-dichlordn1ethyl-4-p-nitrophenylhydroxyrnethyl A -oxa'zoline of M. P. (cap.)'=142143 C; [al 3'7 (0 4% in acetone) and 0.6 c. c. of pure thionyl chloride there is obtained 0.18 g. of D threo Z-dichloracetamido l-p-nitrophenyl-l :3-dic'hl'oropropane identical with'the'product of Example III.

Example V 3 g. 'o'f 'DDe'rythro 2-dichloracetamido-l-p-nitrophenyl- 3-chloropropane 1-ol of M. P. (cap.)=l34 C. are heated'under reflux on the water bath with 12 c. c. of thionyl chloride. The mixture is poured onto crushed ice. After stirring for some time, a granular precipitate is formed which is filtered off, washed with water and dried in vacuo in the presence of potash pellets. There is thus obtained 2.3 g of a product which, after recrystallisation from ethyl acetate and then from alcohol, melts at 135l36 C.

(cap.) and which is identical to that of Example I.

Example VI 'a's'i'n Example-I but starting from 0.5 g. of

L-e'rythro .Z-dichloracetamiclo 1 -.p-nitrophenyl-'3-chloropropane l-ol, of M. P. .(cap.)=ll4-l16 C; {04

4 chloride there is obtained 0.26 g. of D-threo Z-dichloracetamidol-p-nitrophenyl-l:B-dichloropropane identical with the product of Example III.

Example VII 10 g. of DL-t hreo 2-dichloracetamido-l-p-nitrophenylpropane l:3-diol are heated with c. c. of dioxane containing 13% by weight of hydrochloric acid for 3 hours on the boiling water bath. After leaving the reaction mixture to cool, a hydrochloride crystallises which is filtered on. The filtrate is treated with 200 c. c. .of water and a product crystallises which is filtered ofi, washed in water and dried. There is obtained 5 g. of DL-threo Z-dichloracetamido-l-p-nitrophenyl-l :B-dichloroprop'an'e which after recrystallisation in 80% aqueous methyl alcohol is identical with the product obtained in Example I.

Example VH1 15 g. of L-threo Z-dichlbroacetamido-l-p-nitropheriylpropane 1:3-diol of M. P. (cap.)=l51 C.

(c=2.5% in ethanol) is treated as in Example VII with 120 cc. of -dio'xane containing 13% by weight of hydrochloric acid and 5.74 g. of a product is obtained which, after reerystallis'ation in 80% aqueous methanol, is identical with that of Example II.

Example IX 10 g. of DL-threo 2-dichloroa'cetamido-l-p-nitrophenyl-3-chloropropane 1-ol of M. P. (cap.)=l37 C. are heated for 5 hours in a boiling water bath with 50 cc. of dioxane containing 13% by Weight of hydrochloric acid. After being left to cool, the mixture is diluted with water until the turbidity vanishes. A product crystallises 'Which is filtered o'flF, washed with water and 'recrystallised from cc. of 80% aqueous methanol. There is thu's obtained 5.3 g. er a compound which melts at 136-137" C. (cap.) and which is identical with that of Example I.

We claim:

1. The threo forms of Z-dichldracetamido-l-p-nitrophenyl-l 3-dichloropro'pane.

2. DL-threo Z-diChloroacetamido-l-p-nitrophenyl-1:3-

dichloropropane.

3. D-threo 2 dichloracetamido-l-p-nitrophenyl-1:3-dichloropropane.

4. L-threo-Z-dichloracetamido-l-p-nitrophenyl-1,3 dichloropropa'ne.

:5. A process-for the preparation of a threo form of 2-dichloroacetamido-1-p-nitrophenyl-1,3-dichloropropane which comprises heating at a temperature not less than the refluxing temperature of thionyl chloride a 2-dichloromethyl-4-p-nitrophenylhydroxymethyl-A exazoline with a chloride compound of the class consisting of thionyl chloride and hydrogen chloride under anhydrous con- 7. A process according to claim 6 wherein the oxazoline heated is in the-DL erythro form and the resulting compound is in the -DL :threo .form.

8. A process according to claim 6 wherein the oxazoline heated-is in the D erythro form and the resulting compound is in the D threo form.

-9. A process for the preparation of a three .formof Z-diChloracetatmido-l,p-nitrophenyl 1,3- dichloropropane which comprises heating a three form of 2-dichloromethy1-4-p-nitrophenylhydroxymethy1-A -oxazo1ine with hydrogen chloride under anhydrous conditions at about 100 C.

10. A process according to claim 9 wherein the examline heated is in the D-threo form and the resulting dichloro compound is also in the D-threo form.

11. A process according to claim 9 wherein the exam- References Cited in the file of this patent UNITED STATES PATENTS Adams et a1 Apr. 19, 1938 Moersch et a1. July 4, 1950 

1. THE THREO FORMS OF 2-DICHLORACETAMIDO-1-NITROPHENYL-1:3-DICHLOROPROPANE.
 5. A PROCESS FOR THE PREPARATION OF A THREO FORM OF 2-DICHLOROACETAMIDO-1-P-NITROPHENYL-1,3-DICHLOROPROPANE WHICH COMPRISES HEATING AT A TEMPERATURE NOT LESS THAN THE REFULXING TEMPERATURE OF THIONYL CHLORIDE A 2-DICHLOROMETHYL-4-P-NITROPHENYLHYDROXYMETHYL-$2-OXAZOLINE WITH A CHLORIIDE COMPOUND OF THE CLASS CONSISTING OF THIONYL CHLORIDE AND HYDROGEN CHLORIDE UNDER ANHYDROUS CONDITIONS. 